A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme

Joseph J. Cullen, MD, FACS

Status and phase: Completed; Phase 1

Conditions: Glioblastoma; Glioblastoma Multiforme; GBM

Treatments: Drug: Ascorbate; Radiation: Radiation therapy; Drug: Temozolomide

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT01752491

201211713

U01CA140206 (U.S. NIH Grant/Contract)

P30CA086862 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This is a phase 1 (first in man) study testing the safety of adding high dose ascorbate (vitamin C) to standard radiation and chemotherapy for initial treatment of glioblastoma multiforme (GBM).

Full description

This phase 1 study will test the safety of adding high dose ascorbate (vitamin C) to standard chemoradiation and, after the radiation is completed, during 6 cycles of temozolomide.

Standard treatment for glioblastoma multiforme (GBM) involves surgery followed by radiation combined with temozolomide (a chemotherapy). After radiation, patients receive cycles of temozolomide (adjuvant chemotherapy)

Participants will:

• receive high doses of intravenous (IV) ascorbate three times a week during chemoradiation
• receive high doses of intravenous (IV) ascorbate twice a week during adjuvant chemotherapy (after radiation)

This is a phase 1 study will evaluate the side effects of adding this drug to the standard therapy. The dose given to a participant will be determined by how well other participants have tolerated the drug.

Enrollment: 13 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patients must have newly diagnosed (i.e., within 5 weeks), histologically or cytologically confirmed glioblastoma multiforme.

• Diagnosis must be made by surgical biopsy or excision.

• Therapy must begin ≤ 5 weeks after surgery.

• Age ≥ 18 years

• ECOG performance status 0-2 (Karnofsky > 50%).

• A complete blood count and differential must be obtained within 21 days prior to the first dose of radiation, with adequate bone marrow functions as defined below:

  • Absolute neutrophil count (ANC) ≥ 1500 cells per mm3
  • Platelets ≥ 100,000 per mm3
  • Hemoglobin ≥ 8 g/dL

• Serum blood chemistries within 21 days before the first day of radiation, as defined below:

  • Creatinine ≤ 2.0 mg
  • Total bilirubin ≤ 1.5 mg/dL
  • ALT (Alanine Aminotransferase)≤ 3 times the institutional upper limit of normal
  • AST (Aspartate Aminotransferase) ≤ 3 times the institutional upper limit of normal

• Tolerate one text dose (15g) of ascorbate

• Not pregnant

• Ability to understand and willingness to sign a written informed consent document

Exclusion criteria

• Recurrent high grade glioma
• G6PD (glucose-6-phosphate dehydrogenase) deficiency
• Patients actively receiving insulin unless approved by the study medical monitor, study sponsor, and the study principal investigator.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide.
• Significant co-morbid central nervous system disease, including but not limited to, multiple sclerosis.
• Patients who are on the following drugs and cannot have a drug substitution: flecainide, methadone, amphetamines, quinidine, and chlorpropamide. High dose ascorbic acid may affect urine acidification and, as a result, may affect clearance rates of these drugs.
• Prior invasive malignancies (except non-melanomatous skin cancers and carcinoma in situ of the cervix or bladder) unless disease free for ≥ 5 years.
• Patients who have received prior chemotherapy (including Gliadel wafers) for the current glioma.
• Prior radiation therapy to the head or neck, which would result in overlap of radiation therapy fields.
• Patients may not be receiving any other investigational agents.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because ionizing radiation is a known teratogen, and temozolomide is a Class D agent with the potential for teratogenic or abortifacient effects.
• Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4 (an enzyme pathway) inducer, which results in lower serum levels of antiretroviral drugs

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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13 participants in 6 patient groups

15g Ascorbate

Experimental group

Description:

During radiation therapy: * Radiation: 61.2 Gray (1.8 Gray / fraction / day), 5 days/week, for approximately 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once daily, every day, until radiation is completed. * Ascorbate: 15 g administered by IV three times a week until 1 month after radiation is completed (approximately 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.

Treatment:

Drug: Temozolomide

Radiation: Radiation therapy

Drug: Ascorbate

25g Ascorbate

Experimental group

Description:

If the 15g arm is tolerated, the study opens the 25g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 25 g administered by IV three times/wk until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.

Treatment:

Drug: Temozolomide

Radiation: Radiation therapy

Drug: Ascorbate

50g arm

Experimental group

Description:

If the 25g arm is tolerated, the study opens the 50g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 50 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.

Treatment:

Drug: Temozolomide

Radiation: Radiation therapy

Drug: Ascorbate

62.5g

Experimental group

Description:

If the 50g arm is tolerated, the study opens the 62.5g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 62.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.

Treatment:

Drug: Temozolomide

Radiation: Radiation therapy

Drug: Ascorbate

75g Ascorbate

Experimental group

Description:

If the 62.5g arm is tolerated, the study opens the 75g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 75 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.

Treatment:

Drug: Temozolomide

Radiation: Radiation therapy

Drug: Ascorbate

87.5g Ascorbate

Experimental group

Description:

If the 75g arm is tolerated, the study opens the 87.5g arm. During radiation therapy: * Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. * Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. * Ascorbate: 87.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: * Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. * Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.

Treatment:

Drug: Temozolomide

Radiation: Radiation therapy

Drug: Ascorbate